Chest Radiography

Most pleural effusions can be recognized on posteroanterior (greater than 200 mL fluid volume) or lateral (greater than 50 mL fluid volume) chest radiographs. Large effusions may produce contralateral mediastinal shift. Blunting of the costophrenic angle may be the only sign for a small effusion but may also represent pleural thickening.

Thoracic Ultrasound Imaging

The availability of bedside thoracic ultrasound examination by clinicians has had a significant impact on pleural disease management in recent years. The 2010 British Thoracic Society Pleural Disease Guidelines strongly recommended the use of thoracic ultrasound imaging before procedures for pleural fluid. It is particularly useful for the detection (sensitivity approximately 100%), quantification (by depth), and characterization of pleural fluid (Figures 69-1 to 69-3; Table 69-2), as well as for guiding intervention. Ultrasonography is invaluable in the differentiation between pleural fluid and collapsed or consolidated lung, thereby avoiding unnecessary pleural procedures and associated complications.

Figure 69-1 Thoracic ultrasound image demonstrating a large anechoic effusion with compressive atelectasis of underlying lung.

Figure 69-2 A heavily septated effusion is evident on this ultrasound image.

Figure 69-3 Ultrasound appearance strongly suggestive of malignancy, with diaphragmatic nodularity and a large echogenic exudative pleural effusion.

Table 69-2 Pleural Fluid Sonographic Appearances

Thoracentesis guided by clinical examination alone could result in organ puncture in 10% of cases. Several large studies have demonstrated improved safety of pleural interventions performed under ultrasound guidance, particularly in reducing iatrogenic pneumothorax or organ puncture. A Mayo Clinic study showed a dramatic reduction (from 8% to 1%) in rate of thoracentesis-related complications since the unit initiated a “pleural safety program” that included pleural ultrasound training and mandated its use before thoracentesis. With adequate training in this modality, thoracic ultrasound imaging performed by respiratory physicians has been shown to have a safety profile comparable to that when performed by radiologists.

Ultrasound imaging has a high sensitivity (approximately 80%) for detecting pleural malignancy, which can manifest as thickening or nodularity on the visceral, parietal, and diaphragmatic pleural surfaces (see Figure 69-3). Detection of pleural nodularity mandates further investigation (e.g., with chest computed tomography [CT] and pleural biopsy), even if there are no further suspicious features. Ultrasonography also can identify abnormalities beyond the pleural cavity that may provide vital clues to the cause of the effusion, including peripheral lung tumors or abscesses, parenchymal consolidation and atelectasis, diaphragmatic paralysis or elevation, pericardial effusion, and rib and liver metastases and enables evaluation of supraclavicular and cervical lymphadenopathy (Figure 69-4).

Figure 69-4 Neck ultrasound image showing an enlarged, rounded, hypoechoic lymph node characteristic of malignancy, undergoing fine needle aspiration with a 21-gauge needle (*indicates needle tip).

Pleural interventions may be guided by site marking or real-time needle visualization; the latter is required to sample small or loculated effusions. The Royal College of Radiologists (in the United Kingdom), the American College of Chest Physicians, the American College of Surgeons, and the American College of Emergency Physicians are among the many agencies that have published ultrasound training guidelines for clinicians. Appropriate training is essential, because potential pitfalls with performance and interpretation of pleural ultrasound studies are recognized.

Computed Tomography and Magnetic Resonance Imaging

CT with pleural phase contrast enhancement highlights pleural abnormalities and aids discrimination of benign from malignant disease (see Chapter 7). Specific “pleural” CT protocols should be adopted for optimal pleural enhancement and abnormality detection; recent data suggest that images should be acquired 60 seconds after injection of 150 mL of an intravenous contrast agent at 2.5 mL/second. The presence of contraction of the hemithorax, mediastinal pleural involvement, and circumferential pleural thickening (especially greater than 1 cm and with nodularity) all are suggestive of pleural malignancy (Figure 69-5) but cannot adequately differentiate mesothelioma from metastatic pleural cancers. Magnetic resonance imaging (MRI) can help delineate malignant chest wall involvement and is valuable in selected cases, particularly when (probably benign) pleural abnormalities are to be followed clinically by serial imaging in younger patients.

Figure 69-5 Thoracic computed tomography (CT) scan showing circumferential nodular pleural thickening and hemithorax volume loss due to malignant pleural disease.

Positron Emission Tomography

Positron emission tomography (PET)-CT scanning (see Chapter 8) is beginning to emerge as a useful tool in pleural disease management. PET-CT cannot adequately differentiate between benign and malignant effusions, because of the tracer ¹⁸F-fluorodeoxyglucose (FDG). FDG-enhanced PET imaging is confounded by avid pleural uptake of FDG in the presence of pleural inflammation (including that due to previous talc pleurodesis and pleural infection). However, FDG-PET may have a role in guiding pleural biopsy in patients with diffuse pleural abnormality to increase sensitivity (Figure 69-6). FDG-PET also may identify nonpleural sites that allow tissue sampling to confirm malignancy (e.g., lymphadenopathy or liver metastases). Recent data suggest a role for FDG-PET in monitoring disease response to therapy in malignant mesothelioma, as well as a potential prognostic role.

Figure 69-6 Positron emission tomography–computed tomography (PET-CT) image demonstrating localized fluorodeoxyglucose (FDG)-avid mediastinal pleural thickening (arrow) in mesothelioma.

PET scanning using various novel molecular tracers is in early-phase trials for evaluation of pleural malignancies. For instance, PET scanning using labeled thymidine, essential for deoxyribonucleic acid (DNA) synthesis, can identify sites of cell proliferation activity and is not confounded by inflammation (Figure 69-7). New tracers targeting specific cell biology processes (e.g., annexin, a marker of apoptosis) are likely to provide valuable insight to disease pathobiology.

Figure 69-7 Positron emission tomography (PET) imaging using labeled thymidine in a patient with mesothelioma. Images before (A) and after (B) chemotherapy reveal dramatic improvement in the costal and mediastinal pleural uptake with treatment.

(Courtesy Dr. Roslyn Francis, University of Western Australia, Australia.)

Bedside Examination of the Fluid

Most pleural fluids are straw-colored (serous), serosanguineous (blood-stained), or hemorrhagic. A genuine hemothorax is characterized by fluid hematocrit greater than 50% of blood hematocrit.

Appearance of the fluid may reveal the diagnosis: presence of pus confirms empyema; food particles in the fluid suggest esophageal perforation; and chylous fluids suggest chylothorax or pseudochylothorax. Pleural fluid that appears milky should be centrifuged: in empyema, a clear supernatant is seen, whereas chyle remains cloudy. The odor of ammonia often is the most important diagnostic clue to the presence of urinothorax.

Separation of Exudates and Transudates

Exudative pleural effusions most commonly are defined by Light’s criteria (Box 69-1), using the fluid-to-serum ratio of protein and lactate dehydrogenase, which has an accuracy of 96%. Numerous other markers and criteria have been tested (including measurement of pleural fluid cholesterol values), but none has proved superior. Distinguishing exudates from transudates may narrow the scope of the differential diagnosis and streamline further investigations, although such categorization has limitations: It does not provide the diagnosis and fails to identify concurrent transudative and exudative causes of fluid formation. Research in recent years has focused on disease-specific markers that may provide a definitive diagnosis.

Differential Leukocyte Count

The cellular portion of physiologic pleural fluid consists predominantly of macrophages and monocytes. In disease states, the differential cell count of the pleural fluid may be helpful in determining the cause (Box 69-2). Acute pleural inflammation or injury generates chemotaxins, such as interleukin 8, and attracts neutrophils to the pleural space. A neutrophil-predominant effusion is commonly seen with acute bacterial pneumonia or pulmonary infarction. A lymphocyte-rich fluid is more common in disease of insidious onset such as tuberculosis (TB) or malignancy. Tuberculous effusions occasionally (less than 10%) may be neutrophilic. An increased eosinophil count (more than 10% of total leukocytes) is often nonspecific. Most commonly, eosinophil effusions develop secondary to presence of intrapleural air or blood (including pneumothorax or previous interventions) but can also be associated with a range of other diseases, such as Churg-Strauss syndrome or drug-induced pleuritis.

pH and Glucose

Pleural fluid pH (or glucose) measurement can aid disease management. Low glucose levels are associated with a similar spectrum of diseases that give rise to low pH effusions (e.g., infection and connective tissue diseases) (Box 69-3) and are equally informative except in patients with hyperglycemia.

Physiologic pleural fluid pH is approximately 7.6 and reflects bicarbonate accumulation within the pleural cavity. Pleural fluid pH should be measured using a blood gas analyzer, and care should be taken to avoid exposure of the fluid to free air or to residual lidocaine, which will potently raise or lower the fluid pH, respectively. pH meters and litmus paper have been shown to give unreliable values. Low pleural fluid pH (e.g., less than 7.3) coexistent with a normal blood pH may result from increased metabolism of leukocytes, bacteria, or tumor cells or hydrogen ion accumulation.

In malignant pleural effusions, a low pH is associated with more extensive tumor involvement of the pleura, a higher chance of positive findings on cytologic examination, a lower success rate for pleurodesis, and a poorer prognosis. In parapneumonic effusion, a low pH (less than 7.2) predicts the need for chest tube drainage, and pH below 7.2 is now often used as a cutoff point to diagnose pleural infection (complicated parapneumonic effusion) in the presence of a compatible clinical history. A recent study of 308 patients confirmed that pleural fluid pH (or glucose) measurements were superior to other biomarkers tested (pleural fluid procalcitonin, C-reactive protein, lipopolysaccharide-binding protein, and triggering receptor expressed on myeloid cells-1 [sTREM-1]) in distinguishing between simple and complicated parapneumonic effusions.

Disease-Specific Tests

The diagnosis of a malignant effusion should be established only by histocytopathologic confirmation of malignant cells in the pleural fluid or tissue. Pleural fluid cytologic examination is the first line of investigation in suspected cases and has a sensitivity up to 60% (dependent on tumor type, extent of disease, and experience of the cytologist). Immunocytochemical analysis plays an invaluable role in cytologic assessment of pleural fluid, improving the differentiation between benign and malignant effusions and between different malignancies (particularly metastatic adenocarcinoma versus mesothelioma). If malignancy is suspected, generally little incremental benefit is obtained from cytologic analysis of pleural fluid on more than two occasions.

Mesothelioma, the most common primary malignant tumor of the pleura, often is challenging to diagnose. Research in recent years has proposed several potential adjunct diagnostic biomarkers. Mesothelin is a U.S. Food and Drug Administration (FDA)-approved diagnostic and prognostic marker for mesothelioma, although it is not recommended as a sole diagnostic marker (having sensitivity of 48% to 84% and specificity of 70% to 100%). False-negative results may occur with sarcomatoid mesothelioma, which often does not express mesothelin. A raised mesothelin level also can be found with other malignancies (most commonly, pancreatic or ovarian carcinoma but also lung adenocarcinoma and lymphoma). Hence, in patients with elevated pleural fluid or blood mesothelin, further investigations should be considered even if cytologic examination demonstrates no malignant cells. Megakaryocyte-potentiating factor (MPF), which originates from the same precursor protein as for mesothelin, has been shown to have a similar diagnostic performance for detection of mesothelioma. After initial interest in the use of osteopontin for mesothelioma identification, subsequent data have shown it to have a lower diagnostic accuracy than mesothelin.

Other tumor markers and pleural fluid cytokine measurements are neither sensitive nor specific enough for clinical use. Cytogenetic evaluation may be a helpful addition to characterize chromosomal markers of hematolymphoid and mesenchymal malignancies. Flow cytometry of the pleural aspirate should be considered if lymphoma is a possibility.

Gram staining and culture of pleural fluid should be performed in an appropriate clinical setting. Direct inoculation of bottled culture media (“blood culture bottles”) along with separate microbiologic analysis of pleural fluid in a universal container has been shown to increase microbial yield. In cases characterized by presence of frank pus, the diagnosis of empyema is secured, but Gram staining and culture may help to identify the causative organism(s) and to guide therapy.

Testing for tuberculosis should be conducted if clinically indicated, particularly if the fluid is lymphocyte-predominant (more than 50% of total leukocytes). Direct smears and aspirate cultures have low sensitivities (less than 5% and 10% to 20%, respectively) because tuberculous pleuritis usually develops as a type IV hypersensitivity reaction, with low mycobacterial load in the pleural cavity. Demonstration of caseating granulomas by closed or thoracoscopic pleural biopsy clinches the diagnosis. Debate exists regarding the role of adenosine deaminase (ADA), interferon-γ, interferon-γ release assays (IGRAs), and polymerase chain reaction (PCR) techniques in diagnosing tuberculous pleuritis. ADA, an enzyme present in lymphocytes, commonly is measured in disease-endemic countries, and a high pleural fluid ADA level suggests tuberculous effusions, with a sensitivity of greater than 90%. False-positive results have been reported (especially with empyema, rheumatoid effusions, and lymphoma). In nonendemic areas, a low ADA measurement may help rule out tuberculous pleuritis in some patients. Assays for the isoenzyme ADA_2, which predominates in tuberculous effusions, are not widely available. Unstimulated interferon-γ pleural fluid levels perform about as well as ADA for diagnosis in this setting but are more expensive. Peripheral blood and pleural fluid IGRAs have been shown to be of limited clinical value in the diagnosis of tuberculous pleural effusions.

A raised amylase level (above the serum upper limit of normal or if the pleural fluid–to–serum ratio is more than 1) in an appropriate clinical setting can help confirm effusions from esophageal rupture and pancreatic diseases (acute pancreatitis or pseudocyst). Isoenzyme analysis may further differentiate the source of amylase (salivary or pancreatic) but is rarely needed. A raised amylase is present in some malignant (usually adenocarcinomas) effusions.

In suspected cases of chylothorax, lipoprotein electrophoresis for chylomicrons or a triglyceride concentration greater than 1.24 mmol/L (110 mg/dL) confirms the diagnosis. The presence of cholesterol crystals at microscopy with a pleural fluid cholesterol level more than 5.17 mmol/L (200 mg/dL) is diagnostic of a pseudochylothorax. Chylomicrons are not found in pseudochylothorax fluid.

Pleural fluid levels of rheumatoid factor and antinuclear antibody mirror serum values and add little to clinical management of rheumatoid or systemic lupus erythematosus–related pleuritis. Complement levels can be reduced but are of little clinical value. Very low pleural fluid glucose levels typically are seen in patients with a rheumatoid effusion, and differentiation from empyema fluid may be difficult.

β₂-Transferrin is found in cerebrospinal fluid, and its presence in pleural fluid confirms presence of a duropleural fistula. Raised creatinine values are seen in urinothorax.

Percutaneous Biopsy

“Blind” percutaneous pleural biopsy (performed using an Abrams or Cope needle) has been shown to be inferior to imaging-guided biopsy for the diagnosis of malignancy in a randomized controlled trial. Blind biopsy can still be useful in diagnosing diseases with diffuse pleural involvement, especially granulomatous pleuritis (e.g., from TB or rheumatoid arthritis), particularly if thoracoscopic facilities are not readily available. The yield, however, is critically dependent on operator experience and also on the number of passes.

Thoracoscopy

Thoracoscopy is indicated in patients with an undiagnosed exudative pleural effusion after a nondiagnostic thoracentesis. Thoracoscopy can be performed by physicians or surgeons either using local anesthesia and sedation (pleuroscopy) or with the patient under general anesthesia using single-lung ventilation (video-assisted thoracoscopic surgery, [VATS]). Pleuroscopy allows direct visualization of almost the entire pleural surface (Figure 69-9), drainage of fluid, parietal pleural biopsy, and pleurodesis by talc poudrage in the same procedure. Diagnostic sensitivity approaches 95% in malignant pleural diseases and almost 100% in tuberculous pleurisy. Complications are few, and mortality rates low (less than 0.5%). VATS has a similarly high diagnostic sensitivity but also allows other invasive interventions during surgery, including lung biopsy. For details of the technique, refer to Chapter 74.

Figure 69-9 A, Thoracoscopic view into the right pleural cavity showing multiple tumor nodules covering the parietal pleura. B, Thoracoscopy allows identification and biopsy of pleural abnormalities under direct vision while avoiding potentially hazardous structures (e.g., highly vascularized adhesion).

Thoracotomy

Open biopsy with thoracotomy is now seldom indicated. It is a more invasive procedure with significant morbidity, especially postthoracotomy pain.

Thoracentesis

Therapeutic pleural aspiration can be performed at the bedside to relieve breathlessness. For recurrent effusions (e.g., malignant pleural effusions), a definitive procedure to stop fluid reaccumulation, such as pleurodesis, should be considered. If this fails, repeat thoracenteses may be necessary for palliation of breathlessness.

Placement of Indwelling Pleural Catheters

The insertion of a long-term tunneled indwelling pleural catheter (IPC) allows outpatient drainage of refractory malignant pleural effusions. The ambulatory catheters can be inserted as a “day case,” avoiding the need for hospital admission. Its presence induces a complete or partial pleurodesis in up to 70% of patients, and the patient (or the caregiver) can drain the effusion as guided by symptoms, averting hospitalization. Implantation of an IPC also is indicated in patients with a symptomatic effusion and underlying trapped lung, as described later. The catheters usually are well tolerated in clinical practice, but reported complications include development of pleural septations, pleural or soft tissue infection, local tumor invasion at the insertion site, and catheter displacement (Figure 69-10). A randomized trial is under way to evaluate the use of IPCs as first-line therapy in malignant effusions.

Figure 69-10 Magnified chest radiograph demonstrating a left-sided indwelling pleural catheter (IPC), which has become partly displaced and now has a drainage hole within the subcutaneous tissues (arrow).

Insertion of a pleuroperitoneal shunt is another alternative if pleurodesis fails. This intervention is contraindicated in the presence of ascites, and potential complications include infection and shunt occlusion (approximately 10%).

Noninvasive Palliation

In terminally ill patients with symptomatic effusions, use of opiates and oxygen therapy to alleviate breathlessness may be appropriate.

Pleurodesis